Supramolecular M8L6 Nanocage Catalysis of Aqueous Diels-Alder Cycloadditions: Rate Acceleration, Enantioselectivity With Chiral Panels, and Substrate Scope at Neutral pH

This study investigates M8L6 palladium-nanocage acceleration of aqueous Diels-Alder cycloadditions, substrate scope across five diene-dienophile pairs, and enantioselectivity with chiral pyridyl panel ligands at neutral pH within the context of supramolecular chemistry and cage catalysis, an area of growing scientific importance given its implications for green aqueous pharmaceutical synthesis of chiral cycloadducts, catalyst-in-cage recyclability, and supramolecular catalysis design principles for asymmetric reactions. Using NMR and MS cage assembly characterization, kinetics by 1H NMR integration at 2-minute intervals, rate acceleration (kobs/kuncat) measurement for 5 substrate pairs, chiral cage preparation with BINAP-derived panels and chiral HPLC ee determination, we examine hydrophobic substrate concentration inside cage cavity increasing effective molarity 10^3-10^4 fold, with cage Lewis-acidic Pd2+ corners pre-organizing dienophile carbonyl and cage confinement enforcing endo selectivity, amplified for chiral cage by desymmetrized cavity providing asymmetric face discrimination in 5 diene-dienophile substrate pairs at 3 cage loadings (0.5, 2, 10 mol%), 3 temperature conditions (5, 25, 45 C), and chiral cage at 2 mol% for enantioselectivity with n=3 independent reactions per condition drawn from aqueous 50 mM phosphate buffer (pH 7.4) with hydrophobic guest encapsulation assessed by 2D NOESY NMR showing host-guest contact signals for trapped substrates. Results indicate that optimal M8L6 cage achieves kobs/kuncat = 8,420-fold acceleration for anthracene/N-phenylmaleimide pair (best); >99:1 endo selectivity for all substrates; chiral cage achieves 84.2% ee (R product) for cyclopentadiene/oxazolidinone pair at 25 C (p < 0.001), with 8,420-fold rate acceleration; >99:1 endo selectivity; 84.2% ee with chiral cage as the primary quantitative benchmark. Concordance between primary and confirmatory measurement approaches exceeded 93%, validating the analytical framework. These findings contribute empirically to supramolecular chemistry and cage catalysis and carry actionable implications for the design of programs and policies targeting green aqueous pharmaceutical synthesis of chiral cycloadducts, catalyst-in-cage recyclability, and supramolecular catalysis design principles for asymmetric reactions.